Using a biochemical genetic approach, the mutants of chinese hamster ovary cells defective for DN polymerases are being isolated. The mutants are isolated by their resistance to cytosine arabinoside and adenine arabinoside (antitumor and antiviral nucleoside analogs) which are known to be an inhibitor of DNA polymerases. Mutants will also be selected which are resistant to aphidocolin a specific inhibitor of alpha-DNA polymerase. ara-C and ara-A resistant tumors are being characterized for cross-resistance to aphidocolin, likewise aphidocolin-resistant mutants will be examined for cross resistance to ara-A and ara-C, ara-AMP and ara-CMP. Effect of tetrahydroxyuridine and EHNA (specific inhibitor of cytidine and adenine deaminases) on the growth of ara-A and ara-C mutants will be examined and also sensitivity to ara-AMP and ara-CMP as well as to Methylmethanesulformate and ultraviolet light. Additional mutants will be isolated by method of replica plating and in situ assay of DNA polymerases in the animal cells. The mutants resistance to cytosine arabinoside are being characterized for possible defect in DNA polymerases; these mutants are also being characterized for the uptake and metabolic degradation of the drug as well as for other enzyme defect (such as Kinase which can confer drug resistance). The mutants (defective for DNA polymerase) will be characterized biochemically and genetically. Such studies will provide biochemical basis for the understanding of the specific role of the key enzymes (DNA polymerase) in the different aspect of mammalian cell growth and cancer biology (i.e., DNA replication, repair, recombination, and viral expression and integration) during mammalian development.